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Dr. Teichtahl is Director, Department of Respiratory and Sleep Disorders Medicine, Western Hospital.
Correspondence to: Harry Teichtahl, MBBS, FCCP, Western Hospital, Gordon St, Footscray, Victoria, Australia 3011; e-mail: Harry.Teichtahl{at}wh.org.au
The obesity-hypoventilation syndrome (OHS) was originally described in 1955 in subjects with obesity, chronic daytime hypercapnia and hypoxemia, polycythemia, hypersomnolence, and right ventricular failure.1 In 1956, Burwell et al2 coined the term pickwickian syndrome for these patients because they resemble the messenger boy Joe in Charles Dickens’ The Pickwick Papers. OHS is one of the many disease states associated with chronic hypercapnia and alveolar hypoventilation. Lung, neuromuscular, chest wall, and metabolic diseases need to be excluded prior to making a diagnosis of OHS.3 The daytime hypoxemia and raised alveolar-arterial oxygen gradient found in patients with OHS suggest that ventilation-perfusion inequality as well as alveolar hypoventilation is important in this condition.4 With increasing knowledge of the effects of obesity and sleep on respiration, ventilatory control during sleep, and sleep-disordered breathing syndromes, we should be able to further explore the pathogenesis of OHS. Early recognition of OHS patients is important because management options for them have increased substantially in the last few years.
In this issue of CHEST (see page 369), Kessler et al have, in a prospective study, further defined a cohort of OHS patients and have identified differences between this group, those with "pure" obstructive sleep apnea syndrome (OSAS) and those with COPD and OSAS. The study shows that OHS patients were older, more obese, and by definition had more deranged daytime arterial blood gas values, more restricted lung function, more severe arterial oxygen desaturation during sleep, and had higher pulmonary artery pressures and pulmonary vascular resistance than the patients in the pure OSAS group. When comparing the OHS patients to the COPD plus OSAS patients, the former were more obese, had more deranged daytime arterial blood gas values, and more severe arterial oxygen desaturation during sleep then the latter group. Interestingly, the OHS, and COPD plus OSAS patients had similarly raised pulmonary artery pressure and raised pulmonary vascular resistance. Fifty-eight percent of the OHS patients, 36% of the COPD plus OSAS patients, and 9% of the pure OSAS patients had pulmonary hypertension defined as mean pulmonary artery pressure > 20 mm Hg. Twenty-six of the 34 OHS patients studied underwent nocturnal polysomnography, and 23 patients had OSAS with an apnea/hypopnea index > 20/h. Twelve of the 26 OHS patients studied with polysomnography had evidence of central hypopnea, although no quantitative measurements of respiratory effort were made. Kessler et al also show that there is no significant correlation between body mass index and daytime PaCO2 and PaO2 in the three groups of patients. The three patient groups had, on average, severe OSAS with no between-group differences in the apnea index and the apena and hypopnea index. The study has limitations in defining the patient groups and in the methods of measuring pulmonary hemodynamics. For example, only 23 of the 34 OHS patients underwent all the study investigations, 7 of the OHS patients had chronic bronchitis, and pulmonary artery-wedge pressure was not measured. Therefore, some OHS patients may have had coexistent mild COPD, and left ventricular systolic or diastolic dysfunction may have contributed to the pulmonary hypertension found in these patients. The latter is particularly important because of the entity of "obesity cardiomyopathy."5 Notwithstanding these criticisms, the study is well performed and in a large population confirms and adds to previous findings in these patient groups.6 7 8 9 Clinically, the major "take home" messages are as follows: (1) OHS patients have high prevalence of OSAS in addition to nocturnal hypoventilation unrelated to upper-airway obstruction6 8 9 ; (2) pulmonary hypertension is uncommon in pure OSAS patients, especially in the presence of relatively normal daytime arterial blood gas levels6 ; (3) patients with significant COPD plus OSAS and patients with OHS have a high prevalence of pulmonary hypertension7 10 ; (4) the severity of OSAS as measured by AI and AHI does not predict those patients with daytime hypercapnia and hypoxia, whatever the cause11 12 ; (5) patients with OHS have more profound arterial oxygen desaturation during sleep than pure OSAS patients and COPD plus OSAS patients8 ; and (6) COPD is not a prerequisite for the development of OHS.6
A number of questions come to mind regarding OHS, its pathogenesis, and relationship to sleep and OSAS. For example, why do a minority of obese subjects develop OHS? What are the relative contributions of abnormalities of chest wall mechanics, respiratory muscle fatigue, and of ventilatory drive in the development of OHS? What role if any does OSAS play in the pathogenesis of OHS? Can we prevent the development of OHS by recognizing those obese patients who are at risk?
We do not know why only some obese subjects develop OHS, nor do we fully understand its pathogenesis, although it is almost certainly multifactorial in nature. Martin and Sanders3 suggest that OHS is a mixed disorder of "can’t breathe" (chest wall and respiratory muscle disorder) and "won’t breathe" (decreased ventilatory drive disorder). Body weight per se does not correlate with chronic daytime hypercapnia, though weight loss in OHS patients can reverse daytime hypercapnia.13 14 The increased respiratory system elastance and flow-resistive loads seen in obesity do not correlate with the degree of daytime hypercapnia, and some patients with OHS can voluntarily hyperventilate and normalize their PaCO2 when requested to do so.15 16 Reduced chest wall compliance seen in OHS patients can lead to increased energy cost of breathing and reduction in inspiratory muscle strength, maximum voluntary ventilation, and maximal inspiratory pressures.17 18 However, weight loss in OHS patients is associated with increased maximum voluntary ventilation, FVC, and reduced PaCO2, with little change in respiratory system compliance17 and Pankow et al19 have shown that noninvasive positive-pressure ventilation unloads the inspiratory muscles in patients with OHS. These results emphasize the role of respiratory muscle fatigue in patients with OHS.
Ventilatory control is abnormal in OHS patients, with blunting of both hypercapnic and hypoxic ventilatory responsiveness.20 This does not mean that the abnormal ventilatory responses cause the physiologic abnormalities, as they may be secondary phenomena. Indeed, treating OHS patients with either weight reduction, tracheostomy, or nocturnal positive-pressure support improves daytime hypercapnia and hypoxia without changing the abnormal ventilatory responses in some patients.9 In recent years, leptin, a hormone that acts on the hypothalamus to suppress appetite has been shown to be variably increased in obesity.21 Studies22 in genetically obese mice (ob/ob) have shown that genetic determinants related to the ob locus influence hypercapnic ventilatory responsiveness prior to the emergence of obesity. Treating the genetically obese mouse with leptin attenuates the respiratory complications of the obese phenotype.23 Indeed obese mice lacking circulating leptin also exhibit respiratory depression and increased PaCO2, and treatment with leptin increased awake and asleep minute ventilation independently of food intake, weight, and carbon dioxide production.24 These authors postulate that leptin deficiency and/or resistance may play a role in the pathogenesis of conditions with disordered control of breathing such as OHS.25
In normal subjects, ventilation during nonrapid eye movement sleep decreases by 10 to 15% when compared to wakefulness, and in rapid eye movement sleep the changes in ventilation compared to wakefulness are variable.26 27 Becker et al28 have recently shown that minute ventilation in OHS patients is decreased by 21% in nonrapid eye movement sleep and by 39% in rapid eye movement sleep compared to wakefulness, with the majority of the decreased ventilation due to reduced tidal volume. They suggest that in patients with OHS, hypoventilation is an important factor in the genesis of nocturnal hypoxia and that treating the hypoventilation should be a major therapeutic strategy in these patients. The role of OSAS in the genesis of OHS is unclear, and OHS can occur without significant OSAS.14 The majority of patients with OHS, however, will also have evidence of nocturnal upper-airway obstruction, but a causal relationship between OSAS and OHS has not been found to date.8 13 Hypercapnic and hypoxic ventilatory responsiveness in pure OSAS patients have not been well studied, and most studies have assessed these in OSAS patients with daytime hypercapnia.10 12 However, the literature available29 30 does suggest that ventilatory responses are reduced in obese patients with OSAS relative to obese patients without OSAS and nasal continuous positive airway pressure in OSAS patients improves hypercapnic ventilatory responsiveness. However, only about 10 to 15% of patients with OSAS have coexisting daytime hypercapnia and hypoxia, and chronic daytime hypoxemia appears to be a requirement for the development of right-heart failure in patients with OSAS.7
Is it possible from our current knowledge to speculate about a unifying concept for the pathogenesis of OHS? As noted previously, these patients are susceptible to obesity-related respiratory muscle fatigue that may be worsened by coexistent OSAS or increased upper-airway resistance during sleep. In addition, they may either lack circulating leptin and/or have receptor insensitivity to circulating leptin with consequent decreased hypercapnic ventilatory responsiveness. These two mechanisms of "can’t breathe" and "won’t breathe," should they coexist in OHS, would explain the chronic hypoventilation.
We need to identify OHS patients earlier rather than later in their illness and to inform our colleagues about this interesting condition. Early recognition of these patients is important, as appropriate therapy will improve their physiologic and clinical parameters.3 14 Current therapeutic options available for OHS patients are weight loss, continuous positive airway pressure, or bilevel pressure support ventilation, with or without supplemental oxygen, and repeated polysomnography studies may be required to optimize therapy.14 31 32 The challenge for the future is to be able to identify those obese individuals prone to OHS and to prevent its development.
References
This article has been cited by other articles:
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  D. Gozal Determinants of Daytime Hypercapnia in Obstructive Sleep Apnea : Is Obesity the Only One To Blame? Chest, February 1, 2002; 121(2): 320 - 321. [Full Text] [PDF]
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